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Substituted Heterocycles as Therapeutic agents for treating cancer

a heterocycle and cancer technology, applied in the field of tumor suppressor proteins, can solve the problems of difficult development of molecules capable of inhibiting or disrupting the p53/mdm4 interaction

Inactive Publication Date: 2011-12-22
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, in the absence of structural data, such as a high resolution structure of p53 bound to the MDM4 protein, the development of molecules capable of inhibiting or disrupting the p53 / MDM4 interactions is challenging.

Method used

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  • Substituted Heterocycles as Therapeutic agents for treating cancer
  • Substituted Heterocycles as Therapeutic agents for treating cancer
  • Substituted Heterocycles as Therapeutic agents for treating cancer

Examples

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examples

PB1: 6-Chloro-3-[3-cyclopropylmethyl-5-(3,4-dichlorophenyl)-3H-imidazol-4-yl]-1H-indole

[0065]

[0066]6-Chloro-1H-indole3-carbaldehyde (180 mg, 1 mmol) were dissolved in 2 mL of MeOH, and 85.6 μL (1 mmol) cyclopropylmethyl amine was added dropwise. The reaction mixture was stirred for 4 h at room temperature and 1,2-dichloro-4-[isocyano(toluene-4-sulfonyl)methyl]benzene (340 mg, 1 mmol) and piperazine (86 mg, 1 mmol) were added and stirred over night at room temperature. The solvent was evaporated and the crude product purified by chromatography on silica with a gradient of 3:1 to 2:1 heptane / ethyl acetate to yield 6-chloro-3-[3-cyclopropylmethyl-5-(3,4-dichlorophenyl)-3H-imidazol-4-yl]-1H-indole (PB1) 356 mg (86%); 1H-NMR (CDCl3, 600 MHz): δ 0.17 (d, J=4.80 Hz, 2H), 0.54 (d, J=7.86 Hz, 2H), 0.99-1.03 (m, 1H), 3.59 (d, J=6.90 Hz, 2H), 7.07-7.12 (m, 2H), 7.17-7.21 (m, 2H), 7.25-7.26 (m, 1H), 7.46 (m, 1H), 7.74-7.75 (m, 1H), 7.86 (s, 1H), 9.63 (s, 1H); 13C-NMR (CDCl3, 150 MHz): δ 4.0, 11...

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Abstract

MDM2 and MDM4 proteins prevent apoptosis of cancer cells by negatively regulating the transcription factor p53. Compounds according to Formula Iare selective antagonists of MDM2 and MDM4 proteins, disrupting the p53 / MDM2 and p53 / MDM4 complex. These compounds therefore are candidate therapeutics for treating cancer as well as other cell proliferative disease states.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS[0001]This application claims priority to U.S. provisional application Ser. No. 61 / 357,365, filed Jun. 22, 2010, the entire contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The p53 protein is a tumor suppressor protein. Disruption of the genetic machinery encoding this protein or a disruption in the normal physiological function of p53 has been observed to accompany about 50% of all cancers. The p53 protein serves as a checkpoint during cell division and this protein prevents cancers by activating DNA repair proteins, by inducing cell growth arrest, or by initiating apoptosis. The, p53 protein is also implicated to play a role in the development of tumors that become resistant to treatment. It therefore follows that the p53 proteins plays a key role in controlling the progression of cancer.[0003]The ability of p53 to initiate programmed cell death is most often repressed in cancer. Of the variety of...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/12
CPCC07D401/12C07D413/12C07D403/12C07D233/28
Inventor DOEMLING, ALEXANDER
Owner UNIVERSITY OF PITTSBURGH
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